title: The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders.
abstract: BACKGROUND
  The critical role of the activity of the nucleophosmin- anaplastic lymphoma kinase (NPM-ALK) fusion protein in anaplastic large-cell lymphoma prompted drug discovery programs directed against ALK. Drug discovery efforts increased after finding that about 4% of non-small-cell lung cancers (NSCLCs) possess an EML4-ALK fusion protein.
  
  
  METHODS
  The author provides a review of the development of crizotinib, an orally effective c-Met and ALK protein kinase inhibitor. The article highlights its beginning with the X-ray crystallographic structure of a lead compound (PHA-0665752) bound to the active site of the kinase domain of c-Met.
  
  
  CONCLUSIONS
  Studies of patients with EML4-ALK-positive NSCLC showed that crizotinib was clinically effective and led to its approval in August 2011. The use of lipophilic efficiency played a crucial role in the development of crizotinib from a lead c-Met inhibitor. The use of X-ray crystal structures from lead compounds, bound to their targets, is increasing in the drug discovery process owing to its effectiveness. That the drug also inhibits ALK and ALK-fusion proteins was serendipitous, however. The discovery of the EML4-ALK fusion protein in some NSCLC patients has led to the testing and rapid approval of the compound.
authors.affiliation: Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA. rrj@brimr.org
authors.forename: Robert
authors.initials: R
authors.lastname: Roskoski
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D000077547:Crizotinib; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases